Page 72 - JCTR-11-3

Journal of Clinical and
Translational Research N-NOSE: Early cervical cancer screening

invasive cervical cancer), and palliative care. Although to increased ketone body production. Certain ketone
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high-income countries have significantly reduced cervical bodies are known to attract nematodes, 28,40 and their
cancer mortality through robust prevention and treatment presence in urine may explain the observed chemotaxis.
programs, low- and middle-income countries often Further research is needed to determine the precise
lack access to these resources. This disparity contributes relationship between urinary ketone body concentrations
to a disproportionately higher disease burden in these and chemotaxis responses of nematode.
countries, highlighting the urgent need for improved Despite the promising results demonstrated by
global access to preventive and therapeutic measures. 1,9,30 N-NOSE, our study has several limitations that should be
The curability of cervical cancer, when diagnosed at addressed. One of the limitations is the lack of a control
an early stage, underscores the urgent need for highly group (i.e., healthy subjects or non-cancerous individuals)
sensitive, affordable, and non-invasive screening methods to evaluate N-NOSE specificity. However, this study
that can detect CIN before it progresses to invasive focuses on evaluating the sensitivity of the N-NOSE test
cervical cancer. Our study demonstrates the potential in detecting CIN and cervical cancer among diagnosed
of the N-NOSE test – a C. elegans scent-based test using patients. While the absence of a concurrent control group
urine – as a highly sensitive tool for detecting CIN and, is a constraint, it is important to note that the specificity
potentially, early-stage cervical cancer. Notably, previous of the N-NOSE test has been thoroughly established in
studies have demonstrated that N-NOSE is also effective previous large-scale studies involving healthy individuals.
in the early detection of various other cancers, including These studies demonstrated high specificity rates of 90%
biliary tract, gallbladder, esophageal, pancreatic, 32,33 and and 95% using the same cutoff values and methodologies
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gastric cancers. The ability of N-NOSE in identifying employed in our research, 19,22 allowing us to reasonably
early-stage cancer across different types may be attributed infer the specificity of the test within our study population.
to the nematode’s highly evolved sense of smell. 34,35 The N-NOSE test operates based on the chemotaxis
The N-NOSE test leverages the chemotaxis of response of C. elegans, where nematodes are attracted to
C. elegans in response to cancer-related VOCs 21,36,37 and urine samples from cancer patients (positive chemotaxis
has demonstrated higher sensitivity for early-stage cancer index) and repelled by urine samples from subjects without
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detection compared to conventional tumor biomarkers cancer (negative chemotaxis index). The consistent cutoff
such as CEA or CA19-9. This sensitivity may be linked value (0) used in this study is similar to those used in previous
to early metabolic changes in cancer cells, such as the N-NOSE clinical studies, 19,22 reinforcing the relevance
Warburg effect (aerobic glycolysis), 38,39 which often of our study. While high specificity is essential to avoid
precedes or accompanies the epithelial-to-mesenchymal unnecessary interventions, the balance between sensitivity
transition. In addition, cancer cells exhibit upregulation and specificity is crucial for effective screening. 41-43 In this
of other metabolic pathways such as glutaminolysis, regard, N-NOSE emerges as a promising screening tool,
fatty acid synthesis, the pentose phosphate pathway, demonstrating superior sensitivity across various cancers,
and mitochondrial fatty acid oxidation. 38,39 Further particularly for detecting early-stage cancers.
investigation into the specific VOCs detected by C. elegans Our primary objective was to accurately assess the test’s
and their association with various types of cancer may ability to identify true positive cases within a diseased
contribute to the development of more targeted and cohort. The high sensitivity observed – particularly the
effective cancer screening and diagnostic tools. 100% sensitivity in detecting CIN3 lesions – highlights
In this study, significant correlations were observed the test’s potential clinical application for early detection
between the N-NOSE results and specific urinary and intervention. Early identification of CIN is crucial
biomarkers, including glucose (graded as 4+, indicating for preventing its progression to invasive cervical cancer.
concentrations ≥1,000 mg/dL) and ketone bodies. The findings in this study support the N-NOSE test as a
While elevated glucose levels were observed in a small non-invasive, sensitive screening tool with the potential to
subset of patients (4/319), potentially influencing test improve patient outcomes.
results, a previous study suggests that this factor does Translating these prospective findings into real-world
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not significantly impact the overall N-NOSE accuracy. clinical applications requires careful consideration of the
Similarly, significant correlations were observed between inherent challenges associated with detecting disease in
the N-NOSE results and urinary ketone bodies in 16 out of asymptomatic individuals. In these cases, the low signal-
319 patients, encompassing both CIN and cervical cancer to-noise ratio can lead to an overestimation of sensitivity
cases. This finding aligns with the understanding that in studies where cases are pre-identified. 41-43 Real-world
cancer progression can alter energy metabolism, leading screening programs often encounter variability in

Volume 11 Issue 3 (2025) 66 doi: 10.36922/jctr.24.00080